Project Summary/Abstract Although fetal alcohol syndrome was discovered over forty years ago and is entirely preventable, the incidence of fetal alcohol spectrum disorder (FASD) has not diminished. The type and severity of alcohol-induced alterations following prenatal alcohol exposure is strongly impacted by genetics. Dr. Kristin Hamre has demonstrated in BXD recombinant inbred mouse strains with differential vulnerability to FASD that genetics is a principal factor defining susceptibility to alcohol-induced neuron death in the fetal hippocampus, one of the regions central to FASD cognitive deficits. However, the mechanisms behind the genetic contribution has not been identified. Research by Dr. Cynthia Kane has shown that alcohol exposure in the developing brain of C57BL/6J (B6) mice (a parental strain of the BXD lines) produces neuroinflammatory responses that lead to neuron death, including production of pro-inflammatory molecules and glial activation in the hippocampus. Her lab has also found that administration of the peroxisome proliferator-activated receptor-y agonist, pioglitazone, reduces alcohol-induced neuroinflammatory responses in the developing central nervous system. However, the role of genetics in neuroinflammatory responses to developmental alcohol exposure has not been determined. We hypothesize that differential fetal vulnerability to FASD is mediated, at least in part, by genetic differences leading to variation in the neuroinflammatory response to alcohol in the developing hippocampus. Experiments outlined in this proposal will: 1) determine whether alcohol-induced neuroinflammatory responses contribute to the differential genetic vulnerability to alcohol-induced cell loss in the developing hippocampus in Specific Aim 1 and 2) investigate whether administration of the anti-inflammatory drug, pioglitazone, protects highly sensitive BXD strains from hippocampal cell loss by suppressing alcohol-induced neuroinflammatory responses in neonatal mice in Specific Aim 2. The effects will be determined by examining expression of mRNA, expression of protein, percentage of cell loss, and activation of microglia and astrocytes in the hippocampus of neonatal mice exposed to developmental alcohol. This research will result in a further understanding of 1) the genetic contributions to the severity of FASD, 2) the genetic influence of alcohol-induced neuroinflammatory responses, and 3) whether pioglitazone is equally effective at inhibiting alcohol-induced cell loss across animals of differing genetic backgrounds.